PD-1 Blockade Mitigates Surgery-Induced Immunosuppression and Increases the Efficacy of Photodynamic Therapy for Pleural Mesothelioma.

Lung-sparing radical pleurectomy with intraoperative photodynamic therapy (PDT) demonstrates remarkable survival for patients with pleural mesothelioma. Nevertheless, most patients treated with this multimodal approach will develop local tumor recurrence. An understanding of potential causes of treatment failure is central to developing mitigation strategies. Surgery importantly reduces disease burden but also produces tumor-promoting inflammation, as demonstrated through transcriptomic analysis of pleural mesothelioma specimens. Using preclinical models in the setting of combination therapy, we separated the benefit of surgical resection from its counterproductive effects on therapeutic outcome. Specifically, we evaluated mechanisms by which surgically induced inflammation can be therapy-limiting in a murine model of tumor incision (TI) introduced by a surgical cut across the tumor. In this TI model, we identified distinct TI-altered patterns in innate and adaptive inflammatory cells in murine mesothelioma tumors, and we studied changes in these patterns with the addition of PDT. TI introduction of an immunosuppressive environment is established via upregulation of PD-1/PD-L1 expression on tumor cells, T cells, and myeloid cells that is partially resolved by PDT. Immune dysfunction is further mitigated by the addition of PD-1 blockade, leading to curative potential in a process that requires Ly6G+ neutrophils and CD8+ T cells. Overall, these studies suggest that, without PDT, surgical modulation of immune cell trafficking and functionality leads to systemic immunosuppression. This immunosuppressive state potentially interferes with the generation of antitumor immunity by PDT. However, targeted inhibition of surgery-induced signaling in the PD-l/PD-L1 pathway counteracts surgery's immunosuppressive outcomes to enhance PDT efficacy in the intraoperative setting.

Significance: Surgery combined with PDT extends survival for patients with mesothelioma, but these patients are still at risk for tumor recurrence, in part due to the immunosuppressive effects of surgery. We find, in a mouse model, that combining surgery, PDT, and immune checkpoint blockade maximizes the efficacy of these therapies.